M. Manning, W. H. Sawyer and coworkers have published a series of papers describing various [1-(.beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid), 4-valine]arginine-vasopressin congeners which have anti-vasopressin activity. Among these are Nature, 308 652 (1984), as well as U.S. Pat. Nos. 4,367,225 and 4,399,125.
All of the Manning compounds have a peptide tail attached at unit 6 of the disulfide ring. The present compounds are distinguished over these by being hexapeptides which have a basic tail attached to unit 6 and which also have potent vasopressin antagonist activity.
In the description herein and in the claims, the nomenclature common in the art of peptide and vasopressin chemistry is used. When no configuration is noted, the amino acid unit is in the L, or naturally occurring, form. In certain structural formulas, the thio members of the Cap and Cys units are added for clarity.
Certain of the peptide art designations used herein are the following: Cap, .beta.-mercapto-.beta.,.beta.-cycloalkylenepropionic acid; Pmp, .beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid; Tyr(Alk), O-Alktyrosine; Abu, .alpha.-amino-n-butyric acid; Cad, cadaverine; Put, putrescine; Put(G), 1-amino-4-guanidinobutane; Chg, cyclohexylglycine; Cha, cyclohexylalanine; Pba, .alpha.-aminophenylbutyric acid; Gln, glutamic acid amide or glutamine; Gly, glycine; Tyr, tyrosine; Phe, phenylalanine; Phe(4'-Alk), 4'-alkylphenylalanine; N-MeAla, N-methylalanine; Val, valine; Ile, isoleucine; Nle, norleucine; Leu, leucine; Ala, alanine, Lys, lysine; Arg, arginine; Met, methionine; Asn, asparagine; Sar, sarcosine; Tos, tosylate; BHA, benzhydrylamine; DIEA, diisopropylethylamine; 4-MeBzl, 4-methylbenzyl; TFA, trifluoroacetic acid; DCC, dicyclohexylcarbodiimide; Boc, t-butyloxycarbonyl; Z, benzyloxycarbonyl; VSP, vasopressin; HBT, hydroxybenzotriazole; ACM, acetamidomethyl.
"Alk" represents a lower alkyl of 1-4 carbons. For example, these may be optionally attached to the oxygen substituent of a tyrosine unit at position 2 or to the 4'-position of a Phe unit at position 3. Such alkyl substituents include methyl, ethyl, n-propyl, isopropyl or butyl. Ethyl is preferred. When the term, "vasopressin", is used, it means L-arginine vasopressin (AVP) unless otherwise modified. The 1-(.beta.-mercaptocycloalkylene)propionic acid unit (Cap) at position 1 is often referred herein as Pmp for convenience since the pentamethylene containing unit is preferred.